TY - JOUR
T1 - Genome-wide association analysis of radiation resistance in Drosophila melanogaster
AU - Vaisnav, Mahesh
AU - Xing, Chao
AU - Ku, Hung Chih
AU - Hwang, Daniel
AU - Stojadinovic, Strahinja
AU - Pertsemlidis, Alexander
AU - Abrams, John M.
PY - 2014/8/14
Y1 - 2014/8/14
N2 - Background: Ionizing radiation is genotoxic to cells. Healthy tissue toxicity in patients and radiation resistance in tumors present common clinical challenges in delivering effective radiation therapies. Radiation response is a complex, polygenic trait with unknown genetic determinants. The Drosophila Genetic Reference Panel (DGRP) provides a model to investigate the genetics of natural variation for sensitivity to radiation. Methods and Findings: Radiation response was quantified in 154 inbred DGRP lines, among which 92 radiosensitive lines and 62 radioresistant lines were classified as controls and cases, respectively. A case-control genome-wide association screen for radioresistance was performed. There are 32 single nucleotide polymorphisms (SNPs) associated with radio resistance at a nominal p<10-5; all had modest effect sizes and were common variants with the minor allele frequency > 5%. All the genes implicated by those SNP hits were novel, many without a known role in radiation resistance and some with unknown function. Variants in known DNA damage and repair genes associated with radiation response were below the significance threshold of p<10-5 and were not present among the significant hits. No SNP met the genome-wide significance threshold (p = 1.49×10-7), indicating a necessity for a larger sample size. Conclusions: Several genes not previously associated with variation in radiation resistance were identified. These genes, especially the ones with human homologs, form the basis for exploring new pathways involved in radiation resistance in novel functional studies. An improved DGRP model with a sample size of at least 265 lines and ideally up to 793 lines is recommended for future studies of complex traits.
AB - Background: Ionizing radiation is genotoxic to cells. Healthy tissue toxicity in patients and radiation resistance in tumors present common clinical challenges in delivering effective radiation therapies. Radiation response is a complex, polygenic trait with unknown genetic determinants. The Drosophila Genetic Reference Panel (DGRP) provides a model to investigate the genetics of natural variation for sensitivity to radiation. Methods and Findings: Radiation response was quantified in 154 inbred DGRP lines, among which 92 radiosensitive lines and 62 radioresistant lines were classified as controls and cases, respectively. A case-control genome-wide association screen for radioresistance was performed. There are 32 single nucleotide polymorphisms (SNPs) associated with radio resistance at a nominal p<10-5; all had modest effect sizes and were common variants with the minor allele frequency > 5%. All the genes implicated by those SNP hits were novel, many without a known role in radiation resistance and some with unknown function. Variants in known DNA damage and repair genes associated with radiation response were below the significance threshold of p<10-5 and were not present among the significant hits. No SNP met the genome-wide significance threshold (p = 1.49×10-7), indicating a necessity for a larger sample size. Conclusions: Several genes not previously associated with variation in radiation resistance were identified. These genes, especially the ones with human homologs, form the basis for exploring new pathways involved in radiation resistance in novel functional studies. An improved DGRP model with a sample size of at least 265 lines and ideally up to 793 lines is recommended for future studies of complex traits.
UR - http://www.scopus.com/inward/record.url?scp=84905974812&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84905974812&partnerID=8YFLogxK
U2 - 10.1371/journal.pone.0104858
DO - 10.1371/journal.pone.0104858
M3 - Article
C2 - 25121966
AN - SCOPUS:84905974812
SN - 1932-6203
VL - 9
JO - PloS one
JF - PloS one
IS - 8
M1 - e104858
ER -